Metabolic brain disease最新文献

Metabolic dysfunctions such as obesity and diabetes predispose the brain to heightened excitotoxic vulnerability, aggravating neuronal injury and cognitive decline. This study investigated the mechanistic role of lipocalin-2 (LCN2) in metabolic stress-amplified hippocampal damage following kainic acid (KA) exposure. Using high-fat diet (HFD)-fed diabetic wild type (WT) and LCN2 knockout (LCN2KO) mice, we found that LCN2 deficiency improved systemic insulin sensitivity and alleviated hepatic steatosis. In the diabetic hippocampus, LCN2 deletion markedly reduced KA-induced neuronal apoptosis, blood-brain barrier leakage, and iron-mediated oxidative stress. LCN2 ablation suppressed activation of microglia and astrocytes, downregulated galectin-3 and pro-inflammatory cytokines, and inhibited signal transducer and activator of transcription 3 (STAT3)-NF-κBp65-dependent signaling in KA-treated diabetic hippocampus. Reduced autophagy-related protein expression and protein aggregation in KA-treated diabetic LCN2KO mice indicated that LCN2 amplifies excitotoxic stress through autophagic and inflammatory mechanisms. These results identify LCN2 as a pivotal mediator linking metabolic dysfunction to neuroinflammation, ferroptosis, microglial activation, and autophagy in the diabetic hippocampus with excitotoxicity, suggesting that targeting the microglial LCN2-STAT3-NF-κBp65 axis may offer therapeutic potential for metabolic disease-associated acute brain injury.

Chronic ingestion of arsenic frequently occurring in contaminated groundwater poses a serious dual threat to neurological health. Environmental toxicants present in groundwater are highly correlated with onset of neuropathological effects through complex gut-brain axis interactions. The systematic review of literature aims evaluate the neurobehavioural consequences and molecular outcome of a groundwater contaminant, arsenic with microbiota alteration involving animal studies and epidemiological data. Arsenic disrupts the gut microbiota, diminishing beneficial bacteria and promoting harmful strains, which in turn compromise gut barrier integrity, trigger inflammation and oxidative stress, leading to alteration in critical metabolic pathways involved in neurotransmitter production and mitochondrial function. Animal studies have shown that chronic exposure intensifies these effects, causing more pronounced microbial dysbiosis alongside worsened cognitive and behavioural deficits. Mechanistically, arsenic impairs neural signaling by elevating reactive oxygen species, disrupting synaptic and mitochondrial dynamics, and inducing neuroinflammation after its accumulation in brain tissues, while gut-derived neuroactive compounds exacerbate neuroinflammation and neuronal damage irrespective of significant arsenic deposition in the brain. Therapeutic strategies that reinforce gut health, such as targeted probiotic and prebiotic supplementation have demonstrated the ability to restore microbiome balance, strengthen barrier function, reduce neuroinflammatory markers and improve behavioural outcomes in experimental models. These microbiota-focused interventions, when combined with conventional measures like chelation to remove toxic metals and the deployment of water treatment infrastructure in affected regions, suggest a powerful integrated approach. By addressing both the source of contamination and the downstream biological consequences, this multimodal strategy holds significant promise for mitigating arsenic-induced neurotoxicity and protecting at-risk populations in affected communities.

Background the global burden of Parkinson's disease (PD) is rising, yet its pathogenesis remains incompletely understood. Growing evidence implicates the microbiota-gut-brain axis, especially metabolites gut microbiota, as key modulators of PD pathogenesis, but their precise molecular actions remain unclear. Methods using Global Burden of Disease data (1990-2021), we first characterized global epidemiological trends of PD. We identified gut microbiota metabolites and their key targets involved in PD by integrating network pharmacology and molecular docking. Functional enrichment highlighted AKT1 related signaling as a central hub. Finally, Cell Counting Kit 8 (CCK8) assays assessed the neuroprotective effects of selected compounds in 1-methyl-4-phenylpyridinium induced HT-22 neuronal cells. Results global PD prevalence increased from 3,148,395 (1990) to 11,767,272 (2021). Integration of 1,518 gut microbiota metabolite targets with 8,679 PD genes yielded 63 shared targets, among which AKT1, IL6, JUN, TP53, and NFKB1 emerged as hubs. Enrichment analyses highlighted pathways related to inflammation, cellular stress, and apoptosis. Docking suggested favorable IPA-AKT1 binding (-7.553 kcal/mol), and IPA rescued viability in MPP⁺ treated HT‑22 cells (n = 6 per group, mean ± SD; P < 0.05 vs. MPP⁺ control), with significant gains versus MPP⁺ controls (P < 0.05). Conclusion this study integrates epidemiological analysis with computational and experimental approaches to reveal that gut microbiota metabolites, particularly IPA, may influence PD through AKT1 mediated regulation of neuroinflammatory and apoptotic pathways. The insight highlight gut microbiota metabolites as promising candidates for biomarker discovery and therapeutic exploration in PD.

Autism spectrum disorder (ASD) and epilepsy frequently co-occur, yet clinically actionable markers to stratify seizure risk and anticipate drug resistance remain limited. We evaluated whether plasma γ-aminobutyric acid (GABA) and the chloride co-transporters KCC2 and NKCC1, singly and in combination, provide a discriminative signal for ASD status and severity using receiver operating characteristic (ROC) methodology. Forty-six males with ASD and twenty-six age-matched neurotypical controls were phenotyped with the Childhood Autism Rating Scale and Social Responsiveness Scale. Plasma GABA, KCC2, and NKCC1 were quantified by ELISA. Nonparametric tests, logistic regression, and combined ROC analyses were applied. ASD was associated with reduced GABA (0.06 ± 0.04 vs. 0.12 ± 0.05 ng/mL), KCC2 (1.19 ± 1.01 vs. 4.92 ± 3.27 ng/mL), and NKCC1 (8.07 ± 7.08 vs. 10.96 ± 6.72 ng/mL) relative to controls (all p ≤ 0.035), alongside a lower KCC2/NKCC1 ratio (0.193 ± 0.172 vs. 0.525 ± 0.365; p = 0.001). KCC2 and NKCC1 were positively correlated in controls (R = 0.634; p = 0.001), whereas in severe ASD, GABA correlated negatively with KCC2 (R = - 0.638; p = 0.004), consistent with altered chloride homeostasis and GABAergic signaling. Discrimination was highest for KCC2 overall (AUC = 0.931) and in severe ASD (AUC = 0.987); GABA showed good discrimination (AUC = 0.827), and NKCC1 was modest (AUC = 0.664). Marker combinations improved classification: KCC2 + GABA achieved AUC = 0.939 overall and 0.922 in mild-moderate ASD, while GABA + NKCC1 reached AUC = 0.885 in severe ASD. Logistic models yielded odds ratios < 1 across strata, aligning with the observed decrements in ASD. These data indicate that combined ROC analysis of peripheral measures indexing neuronal chloride transport and inhibition provides a robust discriminative signal for ASD stratification and may inform future, mechanism-guided studies of seizure liability and pharmacoresistance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has been implicated in cognitive decline through vascular and metabolic pathways, yet evidence linking it to dementia remains inconsistent. We aimed to determine this association by addressing implications of selection, confounding and reverse causation. We conducted a nationwide, registry-based matched cohort study including all individuals diagnosed with MASLD in Denmark between 2000 and 2020, each with 5 age- and sex-matched references without liver disease. Dementia diagnoses were ascertained through hospital-, prescription-, and death registries. We estimated hazard ratios (HR) using cause-specific Cox regression, adjusting sequentially for comorbidities and socioeconomic status. Sensitivity analyses included age restrictions, delayed entry to address reverse causations, and a negative control outcome (Chronic Obstructive Pulmonary Disease (COPD)) to assess residual confounding from misclassification of alcohol consumption. We included 8,398 individuals with MASLD of which 174 developed dementia during follow-up and 41,990 references of which 641 developed dementia during follow-up. In unadjusted analyses, a MASLD diagnosis was associated with an increased risk of dementia (HR 1.40; 95% CI 1.17 - 1.67). However, the association attenuated after adjustment for comorbidities and socioeconomic factors (HR 1.12; 95% CI 0.94-1.34). Delayed entry analyses suggested possible reverse causation as HRs tended to increase, suggesting underestimation. Using COPD as a negative control outcome showed no increased risk in MASLD patients. Although MASLD was not independently associated with increased dementia risk, our findings suggest possible reverse causation, theoretically reflecting that cognitive decline may cause weight loss, leading to underestimating the association.